EP0994878B1 - Quinolone carboxylic acid derivatives - Google Patents
Quinolone carboxylic acid derivatives Download PDFInfo
- Publication number
- EP0994878B1 EP0994878B1 EP98929898A EP98929898A EP0994878B1 EP 0994878 B1 EP0994878 B1 EP 0994878B1 EP 98929898 A EP98929898 A EP 98929898A EP 98929898 A EP98929898 A EP 98929898A EP 0994878 B1 EP0994878 B1 EP 0994878B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- alkyl
- group
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 125000006414 CCl Chemical group ClC* 0.000 claims abstract description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 9
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 131
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- -1 oxime compound Chemical class 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 21
- 125000006242 amine protecting group Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 229920001429 chelating resin Polymers 0.000 claims description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 238000005932 reductive alkylation reaction Methods 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000003456 ion exchange resin Substances 0.000 claims description 3
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical class CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 230000009257 reactivity Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 26
- 239000003242 anti bacterial agent Substances 0.000 abstract description 10
- 229940088710 antibiotic agent Drugs 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 241000191967 Staphylococcus aureus Species 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 11
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- ZHRGVNZSFKXDKB-UHFFFAOYSA-N tert-butyl 5-methoxyimino-2,7-diazaspiro[3.4]octane-2-carboxylate Chemical compound CON=C1CNCC11CN(C(=O)OC(C)(C)C)C1 ZHRGVNZSFKXDKB-UHFFFAOYSA-N 0.000 description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 7
- 241000192125 Firmicutes Species 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 229940035423 ethyl ether Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 0 CC[C@@](C)(C*(C)=*C1)*1C(C)N(C)C*(C)C Chemical compound CC[C@@](C)(C*(C)=*C1)*1C(C)N(C)C*(C)C 0.000 description 5
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 229960003085 meticillin Drugs 0.000 description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000000676 alkoxyimino group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- MZOITOZMEWAZCZ-UHFFFAOYSA-N tert-butyl 5-ethoxyimino-2,7-diazaspiro[3.4]octane-2-carboxylate Chemical compound CCON=C1CNCC11CN(C(=O)OC(C)(C)C)C1 MZOITOZMEWAZCZ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 2
- ACZDKWIKSVNOHV-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-6-fluoro-7-[5-methoxyimino-2-[(2-methylpropan-2-yl)oxycarbonyl]-2,7-diazaspiro[3.4]octan-7-yl]-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C=2C(=CC(F)=CC=2)F)F)CC11CN(C(=O)OC(C)(C)C)C1 ACZDKWIKSVNOHV-UHFFFAOYSA-N 0.000 description 2
- WKSFHOOAXWKWCS-UHFFFAOYSA-N 1-cyclopropyl-6,8-difluoro-7-(8-methoxyimino-2,6-diazaspiro[3.4]octan-6-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2F)F)CC11CNC1 WKSFHOOAXWKWCS-UHFFFAOYSA-N 0.000 description 2
- QBTBFNPDFJVIHO-UHFFFAOYSA-N 1-cyclopropyl-6,8-difluoro-7-[5-methoxyimino-2-[(2-methylpropan-2-yl)oxycarbonyl]-2,7-diazaspiro[3.4]octan-7-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2F)F)CC11CN(C(=O)OC(C)(C)C)C1 QBTBFNPDFJVIHO-UHFFFAOYSA-N 0.000 description 2
- ZNPOCLHDJCAZAH-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diazaspiro[3.4]octan-6-yl)-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CNC1 ZNPOCLHDJCAZAH-UHFFFAOYSA-N 0.000 description 2
- UQHBTBDJZWXFCX-UHFFFAOYSA-N 1-cyclopropyl-7-[5-ethoxyimino-2-[(2-methylpropan-2-yl)oxycarbonyl]-2,7-diazaspiro[3.4]octan-7-yl]-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound CCON=C1CN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3N=2)C2CC2)F)CC11CN(C(=O)OC(C)(C)C)C1 UQHBTBDJZWXFCX-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- DGDHPCHTWWOQIC-UHFFFAOYSA-N 5-amino-1-cyclopropyl-6,8-difluoro-7-(8-methoxyimino-2,6-diazaspiro[3.4]octan-6-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=C(N)C=2F)F)CC11CNC1 DGDHPCHTWWOQIC-UHFFFAOYSA-N 0.000 description 2
- BYLXNOZAJGVNQA-UHFFFAOYSA-N 6-benzyl-n-methoxy-2,6-diazaspiro[3.4]octan-8-imine Chemical compound C1C2(CNC2)C(=NOC)CN1CC1=CC=CC=C1 BYLXNOZAJGVNQA-UHFFFAOYSA-N 0.000 description 2
- UYPLICSTZSCVEN-UHFFFAOYSA-N 6-benzyl-n-methoxy-2-methyl-2,6-diazaspiro[3.4]octan-8-imine Chemical compound C1C2(CN(C)C2)C(=NOC)CN1CC1=CC=CC=C1 UYPLICSTZSCVEN-UHFFFAOYSA-N 0.000 description 2
- OXNZWNNMJBOZQO-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 OXNZWNNMJBOZQO-UHFFFAOYSA-N 0.000 description 2
- MNTIAYGJHURNSW-UHFFFAOYSA-N 8-chloro-1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diazaspiro[3.4]octan-6-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound CON=C1CN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2F)Cl)CC11CNC1 MNTIAYGJHURNSW-UHFFFAOYSA-N 0.000 description 2
- 125000006519 CCH3 Chemical group 0.000 description 2
- 125000006415 CF Chemical group FC* 0.000 description 2
- 125000006417 CH Chemical group [H]C* 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010041925 Staphylococcal infections Diseases 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- XTRPESAQNDUAQF-UHFFFAOYSA-N [1-benzyl-3-(hydroxymethyl)-4-methoxyiminopyrrolidin-3-yl]methyl methanesulfonate Chemical compound C1C(COS(C)(=O)=O)(CO)C(=NOC)CN1CC1=CC=CC=C1 XTRPESAQNDUAQF-UHFFFAOYSA-N 0.000 description 2
- VRKWXHPZZYFFQY-UHFFFAOYSA-N [3-(azidomethyl)-1-benzyl-4-methoxyiminopyrrolidin-3-yl]methyl methanesulfonate Chemical compound C1C(CN=[N+]=[N-])(COS(C)(=O)=O)C(=NOC)CN1CC1=CC=CC=C1 VRKWXHPZZYFFQY-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- COCAIWZZXYHDND-UHFFFAOYSA-N tert-butyl 7-benzyl-5-ethoxyimino-2,7-diazaspiro[3.4]octane-2-carboxylate Chemical compound C1C2(CN(C2)C(=O)OC(C)(C)C)C(=NOCC)CN1CC1=CC=CC=C1 COCAIWZZXYHDND-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/04—Antibacterial agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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Abstract
Description
- The present invention relates to quinolonecarboxylic acid derivatives having more excellent and broad antibacterial activities than the existing quinolone-series antibiotics. More specifically, it pertains to novel quinolonecarboxylic acid derivatives represented by following formula 1, which have a derivative of 7-[8-(alkoxyimino)-2,6-diazaspiro[3.4]oct-6-yl] as a substituent, and pharmaceutically acceptable salts and isomers thereof:
- Wherein, A is C-H, C-F, C-Cl, C-O-CH3 or N; Y is H or amino; R1 is cyclopropyl or 2,4-difluorophenyl; R2 is C1-4 alkyl; and R3 is H or C1-4 alkyl.
- Quinolonecarboxylic acid derivatives are synthetic antibiotics which are well known to be useful for the treatment of infective diseases in human and animals due to their potent and broad antibacterial activities. Quinolone-series antibiotics such as norfloxacin, ofloxacin and ciprofloxacin are currently used very usefully for the treatment of human diseases and their efficacies are acknowledged. However, these medicines have a problem that: even though they show excellent antibacterial activities against gram-negative bacteria, they still show ordinary or relatively low antibacterial activities against gram-positive bacteria. Accordingly, there have been various studies for solving such problems of existing quinolone-series antibiotics and, finally, sparfloxacin having improved antibacterial activities against gram-positive bacteria has been developed.
- However, this compound still shows weak antibacterial activities against Streptococci, methicillin resistant Staphylococcus aureus(MRSA) and other currently increasing quinolone-resistant strains. These strains are well known as pathogens of the respiratory infections. Therefore. there are increasing needs for the development of improved quinolone antibiotics which exhibit excellent antibacterial activities against such quinolone-resistant strains.
-
-
- Wherein, R is H, methyl or amino; Q is C-H, C-F, C-Cl, C-CH3. C-O-CH3 or N; R1 is cyclopropyl, ethyl, or phenyl substituted with one or more fluorine atoms; R2 is C3-C4 branched alkyl such as t-butyl and cyclopropylmethyl, C3-C6 alkyl having a triple bond such as propagyl and homopropagyl, 2-haloethyl, methoxymethyl, methoxycarbonylmethyl, or a group having the following formula:
-
- Wherein,
- R is H, methyl or amino group;
- Q is C-H, C-F, C-Cl, C-CH3, C-O-CH3 or N;
- R1 is cyclopropyl, ethyl, or phenyl group substituted with one or more fluorine atom;
- R2 is a group of following formula a :
-
- Wherein, X is 2-, 3- or 4-fluoro, cyano, nitro, methoxy, methyl or C1-C4 alkyl group, or 2,4-difluoro group;
- a group of following formula b: ; or
- an arylmethyl group containing a hetero group of following formula c: R3 and R4 are independently H or C1-C3 alkyl group, or they may form a ring with a nitrogen group to which they are attached.
-
- The above compounds are different from the compound of the present invention of the formula 1 in their structures. Specifically, in the compounds disclosed in Korean Patent laid-open publication Nos. 96-873, 96-22501 and 96-22502, and EP688772 A1, an alkoxyimino group is substituted on the pyrrolidine ring, which is a substituent at the 7-position, and the substituents adjacent to the alkoxyimino group such as amino, alkylamino, aminomethyl, alkylaminomethyl are attached to the pyrrolidine ring as a straight chain form. In contrast, in the compounds of the present invention, the pyrrolidine ring substituted at the 7-position having an oxime and its derivatives, forms a diazaspiro compound with an azetidine structure. Accordingly, the compounds of the present invention are different from those of the above patent laid-open publications in their structures. In terms of antibacterial activities, the compounds of the present invention show strong antibacterial activities against the recently-increasing quinolone-resistant strains, while the compounds of the above patent laid-open publications exhibit very weak antibacterial activities against the quinolone-resistant strains.
- Further, although EP265230 A1 discloses the substitution of diazaspiro compound at 7-position of the quinolone derivative. it specifically discloses only 2,7-diazaspiro[4.4]nonane and 2-methyl-2,7-diazaspiro[4.4]nonane compounds of the following formulae and does not specifically disclose 2,6-diazaspiro[3.4]octane compound as disclosed in the present invention. Moreover, there is no mention about the alkoxyimino group introduced in the 2,6-diazaspiro[3,4]octane substituent on the 7-position as disclosed in the present invention. Accordingly, the compounds of the present invention are different from those of the above-mentioned patent laid-open publications in terms of structure. As to antibacterial activities, the compounds of the present invention exhibit excellent antibacterial activities against the existing quinolone-resistant strains as well as against both of gram-negative and gram-positive bacteria, while the compounds of the above-mentioned patent laid-open publications have ordinary antibacterial activities against gram-negative and gram-positive bacteria,
- The present inventors have endeavored constantly to develop novel quinolonecarboxylic acids which exhibit excellent antibacterial activities against both of gram-negative and gram-positive bacteria, as well as improved antibacterial activities against such problematic strains as Streptococci, methicillin resistant Staphylococcus aureus(MRSA) and other currently increasing quinolone-resistant strains.
- Finally, the present inventors have accomplished the present invention by discovering that quinolonecarboxylic acids substituted with 7-[8-(alkoxyimino)-2,6-diazaspiro[3,4]oct-6-yl] at the 7-position show excellent antibacterial activities against the above-mentioned strains.
- Accordingly, it is an object of the present invention to provide novel quinolonecarboxylic acid derivatives of the above formula 1, and pharmaceutically acceptable salts and isomers thereof, which exhibit excellent antibacterial activities against both of gram-negative and gram-positive bacteria and, especially, show superior antibacterial activities against the methicillin-resistant strains, as well as against the existing quinolone-resistant strains.
- Another object of the present invention is to provide processes for preparing the novel quinolonecarboxylic acid derivatives of the formula 1.
-
- Wherein, A is C-H, C-F, C-Cl, C-O-CH3 or N; Y is H or amino; R1 is cyclopropyl or 2,4-difluorophenyl; R2 is C1-4 alkyl; and R3 is H or C1-4 alkyl.
- The present invention is described in more detail as follows.
- According to the present invention, the typical examples of quinolone carboxylic acid derivatives of the above formula 1 may be listed as follows:
- 1-cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3.4]oct-6-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
- 1-cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3.4]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-cyclopropyl-6,8-difluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-cyclopropyl-6-fluoro-8-chloro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4] oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-cyclopropyl-5-amino-6,8-difluoro-7-[8-(methoxyimino)-2,6-diazaspiro[ 3,4]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-(2,4-difluorophenyl)-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]o et-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-(2,4-difluorophenyl)-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3.4]o ct-6-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
- 1-cyclopropyl-6-fluoro-7-[8-(ethoxyimino) -2,6-diazaspiro[3.4]oct-6-yl]-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
- 1-cyclopropyl-5-amino-6,8-difluoro-7-[8-(ethoxyimino)-2,6-diazaspiro[3.4 ]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-cyclopropyl-6-fluoro-7-[8-(methuxyimino)-2-methyl-2,6-diazaspiro[3.4] oct-6-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,
- 1-cyclopropyl-6-fluoro-7-[8-(methuxyimino)-2-methyl-2.6-diazaspiro[3,4] oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-cyclopropyl-6,8-difluoro-7-[8-(methoxyimino)-2-methyl-2,6-diazaspiro[ 3,4]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,
- 1-cyclopropyl-6-fluoro-8-chloro-7-[8-(methoxyimino)-2-methyl-2,6-diaz aspiro[3,4]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, and
- 1-cyclopropyl-5-amino-6,8-difluoro-7-[8-(methoxyimino)-2-methyl-2,6-d iazaspiro[3,4]oct-6-yl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.
-
- The quinolonecarboxylic acid derivatives of the, present invention represented by formula 1 have a double bond in the pyrrolidine ring at the 7-position and, accordingly, geometric isomers of cis- or trans-form may be present. The present invention includes all of such geometric isomers.
- A pharmaceutically acceptable salt may be prepared from the quinolonecarboxylic acid derivatives of the present invention represented by formula 1, in accordance with some ordinary methods in the art to which the present invention pertains. As one kind of such salt, an acid addition salt may be prepared, and exemplary acids to be used therefor include an inorganic acid such as hydrochloric acid, phosphoric acid and sulfuric acid; and an organic acid such as methane sulfonic acid, p-toluene sulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid and glucuronic acid. In addition, a cation such as sodium or potassium ion may also be used for the preparation of pharmaceutically acceptable salts.
- Further, the present invention includes the process of preparing the quinolonecarboxylic acid derivatives represented by formula 1.
- The quinolonecarboxylic acid derivatives of the present invention of the formula 1 may be prepared by any one of two methods represented by the following Reaction schemes 1 and 2.
-
- Wherein, A, Y, R1, R2 and R3 are respectively as definded above, and X is a halogen atom, preferably, fluorine or chlorine. The compound of formula 2 may be prepared in accordance with the method described in U. S. Patent No. 4,382,892. The compound of formula 3 may be used in the form of a free base or an acid salt, and the acid salt may be formed by using an acid such as hydrochloric acid, acetic acid and trifluoroacetic acid.
- To explain the above reaction scheme in more detail, the coupling reaction of the compound of formula 2 with the compound of formula 3 is carried out under the presence of a solvent with the addition of a suitable base(acid acceptor) to obtain a quinolonecarboxylic acid derivative represented by formula 1. The reaction may be completed preferably at 0 to 200°C for 1 to 24 hours with stirring.
- As the solvent used in the above reaction, acetonitrile, dimethyl formamid(DMF), dimethylsulfoxide(DMSO) and pyridine are preferred. As the base(acid acceptor), it is preferred to use inorganic bases such as sodium hydrogencarbonate, calcium carbonate, and sodium carbonate, or organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, N,N-dimethylaniline, N,N-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), 1,5-diazabicyclo[4,3,0]nonene-5(DBN), and 1,4-diazabicyclo[2,2,2]octane(DABCO). Further, the reaction efficiency may be increased by using an excessive amount(2 to 10 mole equivalents) of the compound of formula 3 as an acid acceptor. The reaction rate may increase by using an ion-exchange resin. Exemplary ion-exchange resin may include Amberlite® IRA-420, Amberlite® IRA-900 and Amberlite® IRA-64.
- In the second preparation process(Reaction scheme 2), a compound of the following formula 2 is subjected to a coupling reaction with a compound of the following formula 3a to prepare the desired compound of the present invention, i.e., a compound represented by the following formula 1 wherein R3 is H, via an intermediate of the following formula 4. Further, the compounds of formula 1 wherein R3 is C1-4 alkyl may be prepared by reductive alkylation of the compounds of formula 1 wherein R3 is H with lower aldehydes.
- Wherein, A, X, Y, R1, R2 and R3 are respectively as definded above, and P is an amine protecting group.
- The compound of formula 3a may be used in the form of a free base or an acid salt, and the acid salt may be formed by using an acid such as hydrochloric acid, acetic acid and trifluoroacetic acid. Further, exemplary amine protecting groups(P) of the compound of formula 3a include formyl, acetyl, trifluoroacetyl, benzoyl, alkoxycarbonyl(e.g., ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl), benzyl, p-methoxybenzyl and trityl.
- The above reaction is carried out under the same conditions as illustrated in Reaction scheme 1 for the coupling reaction of the compound of formula 2 with the compound of formula 3. The amine protecting group(P) of the compound of formula 4 thus obtained from the condensation reaction is removed by an alkali hydrolysis or a general deprotection reaction to obtain the compound of formula 1.
- For example, the compound of formula 4 is reacted in a solvent under the presence of an acid or base at a temperature ranging from room temperature to 120°C to remove the amine protecting group(P). As an acid for use in the deprotection reaction, an inorganic acid such as hydrochloric acid, bromic acid and sulfuric acid, or an organic acid such as acetic acid, trifluoroacetic acid, formic acid, p-toluenesulphonic acid may be used. Further, in case that the amine protecting group(P) is a benzyl, p-methoxybenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or trichloroethoxycarbonyl group, the amine protecting group(P) may be removed by the reduction under the hydrogen atmosphere at a temperature ranging from 5 to 100°C using palladium, Raney nickel or platinum.
- On the other hand, the compounds of formula 1 wherein R3 is C1-4 alkyl may be prepared by reductive alkylation of the compounds of formula 1 wherein R3 is H with C1-4 aldehyde under a weak acidic condition by using sodiumcyanoborohydride as a reducing agent at 0 to 50°C.
-
- Wherein, R2 and R3 are as defined above; L is methanesulfonyloxy, p-toluenesulfonyloxy, or halogen, preferably fluorine or chlorine; and P' is an amine protecting group such as formyl, acetyl, trifluoroacetyl, benzoyl, alkoxycarbonyl(e.g., ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl), benzyl. p-methoxybenzyl and trityl.
- To explain the process of Reaction scheme 3 in detail, a ketoester compound(formula 5) is reacted with an aqueous formalin solution at 0 to room temperature under the presence of a base to obtain a hydroxyketone compound(formula 6). Suitable bases for this reaction include sodium carbonate, calcium carbonate, sodium hydrogen carbonate, sodium hydroxide and calcium hydroxide, and suitable solvents include alcohols such as methanol, ethanol and isopropyl alcohol. The compound of formula 6 is reacted with an alkoxylamine to obtain an alkoxyimino pyrrolidine derivative compound of formula 7 in high yields. In this reaction, pyridine may be used as a solvent, as well as a base. Further, in case that water, tetrahydrofuran or an alcohol(methanol, ethanol, etc.) is used as a solvent, an inorganic base such as sodium hydrogen carbonate and sodium acetate may also be used together with such solvent. In order to convert an hydroxy group(-OH) in the compound of formula 7 to a suitable leaving group L[methanesulfonyloxy(-OMs), p-toluenesulfonyloxy(-OTs), halogen], the hydroxy group is reacted with methanesulfonyl chloride or p-toluenesulfonyl chloride under the presence of an organic base such as triethylamine and pyridine at a temperature ranging from 0 to 50°C to obtain the compound of formula 8 wherein the hydroxy group is substituted with leaving group L. On the other hand, the compound of formula 8 may also be obtained by converting the hydroxy group(-OH) in the compound of formula 7 to halogen according to a conventional method. In the representative example of such halogenation reaction, pyridine is added to triphenylphosphine and carbontetrabromide(J. Chem. Soc, Perkin Trans. 1, 3549, 1997) and then reacted with the compound of formula 7 to obtain the bromide compound of formula 8. The ester group of the compound of formula 8 thus obtained is reduced by using a suitable reducing agent at a temperature ranging from 0 to reflux temperature of used solvent to obtain the alcohol compound of formula 9 in a good yield. Representative reducing agent for this reaction is sodium borohydride and the reactivity of sodium borohydride increases by using it together with a lithium salt(lithium chloride or lithium bromide). When sodium azide is reacted with leaving group L in the compound of formula 9, an azidomethyl pyrrolidine compound(formula 10) is obtained. As a solvent for this reaction, dimethyl formamide(DMF) or dimethyl sulfoxide(DMSO) is preferred. In order to convert a hydroxy group in the azidomethyl pyrrolidine compound(formula 10) to a suitable leaving group L[methanesulfonyloxy(-OMs), p-toluenesulfonyloxy(-OTs) or halogen], the same reaction as in the conversion of the compound of formula 7 to the compound of formula 8 is conducted under the same conditions to obtain the compound of formula 11 wherein the hydroxy group is converted to a leaving group L, in a good yield. The azido group in the compound of formula 11 is reduced by using a metal catalyst such as platinum, palladium on carbon(Pd/C) and Raney nickel, or reduced by using triphenylphosphine or triphenylphosphite in an inert solvent such as tetrahydrofuran to obtain aminomethyl pyrrolidine compound(formula 12) in a good yield. When the compound of formula 12 is heated at 50 to 130°C under the presence of a suitable base, a cyclization reaction occurs to obtain 8-alkoxyimino-2,6-diazaspiro[3,4]octane derivative compound of formula 13. As a solvent for use in this reaction, acetonitrile, dimethylformamide, pyridine and toluene are preferred, and preferred bases include organic bases such as triethylamine, diisopropylamine, pyridine, lutidine, N,N-dimethylaniline, N,N-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), 1,5-diazabicyclo[4,3,0]nonene-5(DBN) and 1,4-diazabicyclo[2,2,2]octane(DABCO). The amine protecting group P' in the compound of formula 13 is removed, according to the kind of amine protecting group, under the same conditions as in the deprotection reaction of the amine protecting group P, which reaction is used for the preparation of the compound of formula 1 from the compound of formula 4 as illustrated in Reaction scheme 2, to obtain the compound of formula 3 wherein R3 is H. On the other hand, the compound of formula 3 wherein R3 is C1-4 alkyl may be prepared by subjecting the exposed amine in the compound of formula 13 to a reductive alkylation reaction by using sodium cyanoborohydride as a reducing agent under weak acidic conditions with C1-4 aldehyde, and then removing the amine protecting group P', according to the kind of amine protecting group, under the substantially same conditions as in the deprotection reaction of the amine protecting group P, which reaction is used for the preparation of the compound of formula 1 from the compound of formula 4 as illustrated in Reaction scheme 2. Further, the compound of formula 3a, which is another starting material used in Reaction scheme 2 may be prepared by introducing an amine protecting group P, which is the same kind of protecting group as the previously defined amine protecting group P', into the compound of formula 13 to obtain the compound of formula 14 and, then, removing the amine protecting group P' in accordance with a suitable deprotection method selected from the previously presented deprotection methods depending on the kind of the amine protecting group.
- The following Preparation Examples and Examples are intended to further illustrate the present invention without limiting its scope
- 50g of 1-benzyl-4-ethoxycarbonyl-pyrrolidine-3-one was dissolved in 300ml of isopropanol and thereto 4ml of 10% NaOH and 20.7ml of formalin were added successively. The mixture was stirred for 30 minutes at room temperature and concentrated under reduced pressure. 200ml of water was added to the concentrated residue. The resulting solution was extracted twice with each 200ml of ethylether, dried with magnesium sulfate, filtered and concentrated under reduce pressure to give 46g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one(yield : 82.0%). The obtained compound was dissolved in 400ml of pyridine and thereto methoxylamine hydrochloride was added and stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with 400ml of dichloromethane, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure to give 43g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxi me(yield : 84.6%). Thus obtained compound was dissolved in a solution of 22ml of triethylamine and 400ml of dichloromethane and cooled to 0-5°C and thereto 10ml of methanesulfonylchloride was added dropwise and the reaction temperature was slowly increased up to room temperature. The reaction mixture was stirred for 1 hour, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure to give 50g of 1-benzyl-4-methanesulfonyloxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O -methyloxime(yield: 92.6%). It was dissolved in 200ml of tetrahydrofuran and thereto 13g of sodium borohydride and 400ml of ethyl alcohol were added successively at room temperature and 11g of lithium chloride was added slowly. The reaction mixture was stirred for 5 hours and poured into 300ml of ice water. The resulting solution was adjusted to pH 5-6 with diluted hydrochloric acid, concentrated under reduced pressure to remove most organic solvents therefrom, then extracted twice with each 200ml of ethylether, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silicagel column chromatography(ethylacetate:normal hexane=2:1) to give 42g of the titled liquid compound(yield : 94.3%).
1H-NMR(CDCl3, ppm): 2.54(d, 1H), 2.84(d, 1H), 2.96(s, 3H), 3.30(s, 2H), 3.60 ∼3.71(m, 4H), 3.77(s, 3H), 4.32∼4.53(m, 2H), 7.22∼7.27(m, 5H). - 42g of 1-benzyl-4-methanesulfonyloxymethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime was dissolved in 400ml of dimethylformamide and thereto 21g of sodium azide was added and the resulting solution was stirred for 6 hours at 110°C. The reaction mixture was concentrated under reduce pressure, diluted with 300ml of ethylether, washed twice with each 200ml of water and twice with each 200ml of saline solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure to give 31g of
1-benzyl-4-azidomethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime (yield : 87.3%). The obtained compound and 18ml of triethylamine were added into 300ml of dichloromethane and cooled to 0-5°C, and thereto 9.0ml of methanesulfonylchloride was slowly added dropwise. The reaction temperature was increased up to room temperature and the mixture was stirred for 1 hour. The reaction mixture was washed with 200ml of water and 200ml of saline solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure and the concentrated residue was purified by silicagel column chromatography (ethylacetate:normal hexane=1:3) to give 38.8g of the titled compound(yield: 98.4%).
1H-NMR(CDCl3, ppm): 2.77(d, 2H), 2.98(s, 3H), 3.34(s, 2H), 3.57(s, 2H), 3.65(s, 2H), 3.85(s, 3H), 4.31(s, 2H), 7.22∼7.27(m, 5H). - 10g of 1-benzyl-4-methanesulfonyloxymethyl-4-azidomethyl-pyrrolidine-3-one-O-methyloxime was dissolved in 100ml of ethyl acetate and thereto 5ml of 50% Raney nickel slurry was added and the resulting mixture was stirred for 3 hours under the pressure of hydrogen. The reaction mixture was filtered and concentrated under reduced pressure to give 8.0g of 1-benzyl-4-methanesulfonyloxymethyl-4-aminomethyl-pyrrolidine-3-one-O-methyloxime(yield: 86%). The obtained compound was dissolved in 200ml of acetonitrile and thereto 3.9ml of 1,8-diazabicyclo[5,4,0]undec-7-ene was dropped, and the resulting mixture was stirred for 8 hours, concentrated under reduce pressure, and dissolved in 150ml of dichloromethane, washed with 100ml of water and with 100ml of saline solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure to give 4.0g of 6-benzyl-2,6-diazaspiro[3,4]octane-8-one-O-methyloxime(yield: 69.3%). The obtained compound and 2.5ml of triethylamine were dissolved in 50ml of dichloromethane and thereto 3.9g of di-t-butyldicarbonate. The resulting mixture was stirred for 4 hours, washed with 50ml of water, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified by silicagel column chromatography (ethylacetate:normal hexane:dichloromethane=3:5:1) to give 4.6g of the titled compound(yield: 80.9%).
1H-NMR(CDCl3, ppm): 1.36(s, 9H), 2.80(s, 2H), 3.24(s, 2H), 3.51(s, 2H), 3.78(d, 2H), 3.80(s, 3H), 4.24(d, 2H), 7.20∼7.27(m, 5H). - 4.0g of t-butyl-6-benzyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate was dissolved in 40ml of methanol and thereto 4.0g of 10% Pd-C was added. The resulting mixture was stirred for 2 hours under the pressure of hydrogen at 5°C, filtered and concentrated under reduced pressure to give 1.3g of the titled compound(yield : 87.9%).
1H-NMR(CDCl3, ppm): 1.39(s, 9H), 3.18(s, 2H), 3.58(s, 2H), 3.78(d, 2H), 3.80(s, 3H), 4.05(d, 2H). - The titled compound was prepared by the same procedure as Preparation 1.
1H-NMR(CDCl3, ppm): 1.21(t, 3H, J=7.07Hz), 2.92(bs, 2H), 3.03(bs, 2H), 3.40(m, 2H), 3.72∼3.75(m, 4H), 4.05∼4.11(m, 2H), 4,35∼4.42(m, 2H), 7.26 ∼7.33(m, 5H). - The titled compound was prepared by the same procedure as Preparation 2.
1H-NMR(CDCl3, ppm): 1.14(t, 3H, J=7.08Hz), 2.63∼2.72(dd, 2H, J=9.48Hz), 2.91(s, 3H), 3.29(s, 2H), 3.51(s, 2H), 3.58(s, 2H), 4.04(q, 2H, J=7.08Hz), 4.28(s, 2H), 7.24(m, 5H). - The titled compound was prepared by the same procedure as Preparation 3.
1H-NMR(CDCl3, ppm): 1.19(m, 3H), 1.41(s, 9H), 2.85(bs, 2H), 3.30(bs, 2H), 3.64(bs, 2H), 3.80(bs, 2H), 4.07∼4.11(m, 4H), 7.30(bs, 5H). - The titled compound was prepared by the same procedure as Preparation 4.
1H-NMR(CDCl3, ppm): 1.20(t, 3H, J=6.84Hz), 1.38(s, 9H), 3.32(s, 2H), 3.62(s, 2H), 3.88(d, 2H), 4.10∼4.19(m, 4H), 4.97(s, 1H). - 550mg of 6-benzyl-2,6-diazaspiro[3,4]octane-8-one-O-methyloxime was added to 10ml of ethanol and thereto 0.4ml of acetic acid and 176mg of paraformaldehyde were added and the resulting mixture was stirred for 30 minutes at room temperature and thereto 370mg of sodium cyanoborohydride was added. The resulting mixture was stirred for 16 hours at room temperature, neutralized with aqueous solution of potassium carbonate and distilled under reduced pressure and the obtained residue was added into 50ml of dichloromethane, washed with 50ml of water, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silicagel column chromatography(methanol:normal hexane:dichloromethane=1:10:8) to give 350mg of the titled compound(yield: 60.1%).
1H-NMR(CDCl3, ppm): 2.38(s, 3H), 2.87(s, 2H), 3.19(s, 2H), 3.23(d. 2H), 3.29(d, 2H), 3.58(s, 2H), 3.89(s, 3H), 7.17∼7.27(m, 5H). - 340mg of 6-benzyl-8-(methoxyimino)-2-methyl-2,6-diazaspiro[3,4]octane was dissolved in 10ml of methanol and thereto 300mg of 10% Pd-C was added. The resulting mixture was stirred for 2 hours at 50°C under the pressure of hydrogen, filtered and concentrated under reduced pressure to give 195mg of the titled compound(yield: 85.2%).
1H-NMR(CDCl3, ppm): 2.33(s, 3H), 3.23∼3.28(m, 4H), 3.35(d, 2H), 3.56(s, 2H), 3.86(s, 3H). - 400mg of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carb oxylic acid and 840mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10ml of acetonitrile and the resulting mixture was stirred for 3 hours at 45-50°C. Then the precipitated solid was filtered and dried to give 650mg of the titled compound(yield:93.9%).
m.p. : 278-279°C
1H-NMR(CDCl3, ppm): 1.05(m, 2H), 1.27(m, 2H), 1.45(s, 9H), 3.61∼3.67(m, 1H), 3.90(s, 3H), 3.94(s, 2H), 4.25(s, 2H), 4.27(s, 2H), 4.56(s, 2H), 8.04(d, 1H, J=11.71Hz), 8.68(s, 1H). - 400mg of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 840mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10ml of acetonitrile and the resulting mixture was refluxed for 3 hours. Then the precipitated solid was filtered and dried to give 340mg of the titled compound(yield: 46.4%).
m.p. : 255∼256°C
1H-NMR(CDCl3, ppm): 1.18(bs, 2H), 1.39(m, 2H), 1.45(s, 9H), 3.52(bs, 1H), 3.91∼4.05(m, 7H), 4.27(d, 2H), 4.34(s, 2H), 7.00(d, 1H, J=7.07Hz), 7.94(d, 1H, J=13.67Hz), 8.64(s, 1H). - 150mg of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 320mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10ml of acetonitrile and the resulting mixture was refluxed for 7 hours and then cooled to room temperature. The precipitated solid was filtered and dried to give 120mg of the titled compound(yield: 55.5%).
m.p. : 255∼256°C
1H-NMR(CDCl3, ppm): 1.16(s, 2H), 1.29(d, 2H), 1.44(s, 9H), 3.92∼3.94(m, 6H), 4.05(s, 2H). 4.22(d, 2H). 4.38(s, 2H), 7.89(d, 1H), 8.76(s, 1H). - 300mg of 1-cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 530mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2g of Amberlite® IRA-420 were added to 10ml of acetonitrile and thereto 1ml of triethylamine was added dropwise. The resulting mixture was refluxed for 72 hours and then the resulting solid was filtered off. The filtrate was concentrated under reduced pressure and thereto 10ml of ethylacetate was added and the resulting solution was stirred for 4 hours. The precipitated solid was filtered and dried to give 169mg of the titled compound(yield: 31.4%).
m.p. : 203 ∼ 204°C
1H-NMR(CDCl3, ppm): 1.16(bs, 2H), 1.39(d, 2H), 1,44(s, 9H), 3.92∼3.94(m, 6H), 4.03(s, 2H), 4.21(d, 2H), 4.38(s, 2H), 7.88(d, 1H, J=13.19Hz), 8.76(s, H). - 750mg of1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 1.05g of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 4g of Amberlite® IRA-420 were added to 20ml of acetonitrile and thereto 2ml of triethylamine was added dropwise. The mixture was refluxed for 5 5 days and then 2ml of dimethylformamide was added thereto. The resulting mixture was stirred for 1 hour and the thus precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and then to the resulting residue 10ml of acetonitrile was added and stirred for 1 hour. The precipitated solid was filtered and dried to give 420mg of the titled compound(yield: 30.9%).
m.p. : 256∼257°C
1H-NMR(CDCl3, ppm): 1.05(s, 2H), 1.18(d, 2H), 1,44(s, 9H), 3.89∼3.96(m, 6H), 3.99(s, 2H), 4.21(d, 2H), 4.34(s, 2H), 8.62(s, 1H). - 95mg of 1-(2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 120mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 400mg of Amberlite® IRA-420 were added to 10ml of acetonitrile and thereto 0.5ml of triethylamine was added dropwise. The resulting mixture was refluxed for 48 hours and the thus precipitated solid was filtered off. To the filtrate 5ml of ethylether was added and the resulting mixture was stirred for 4 hours. The precipitated solid was filtered and dried to give 110mg of the titled compound(yield: 67.8%).
m.p. : 263∼264°C
1H-NMR(CDCl3, ppm): 1,43(s, 9H), 3.64(s, 2H), 3.86∼3.91(m, 2H), 3.92(s, 3H), 4.18∼4.21(m, 4H), 5.91(d, 1H, J=6.84Hz), 7.18∼7.24(m, 2H), 7.48(m, 1H), 8.06(d, 1H, J=13.68), 8.54(s, 1H). - 110mg of 1-(2,4-difluorophenyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 120mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10ml of acetonitrile and thereto 0.5ml of triethylamine was added dropwise. The resulting mixture was stirred for 4 hours at 50°C and then for 2 hours at room temperature. The precipitated solid was filtered and dried to give 150mg of the titled compound(yield: 79.9%).
m.p. : 230∼232°C
1H-NMR(CDCl3, ppm): 1.47(s, 9H), 3.82∼3.92(m, 7H), 4.17∼4.29(m, 4H), 7.07∼7.13(m, 2H), 7.35∼7.41(m, 1H), 8.12(d, 1H, J=12.20Hz), 8.64(s, 1H). - 360mg of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 500mg of t-butyl 8-(ethoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10ml of acetonitrile and thereto 1ml of triethylamine was added dropwise. The resulting mixture was stirred for 2 hours at 50°C and then for 1 hour at room temperature. The precipitated solid was filtered and dried to give 380mg of the titled compound(yield: 57.9%).
m.p. : 261∼262°C
1H-NMR(CDCl3, ppm): 1.06(s, 2H), 1.27∼1.31(m, 5H), 1.45(s, 9H), 3.64∼ 3.66(m, 1H), 3.96(d, 2H), 4.19∼4.28(m, 6H), 4.57(s, 2H), 8.08(d, 1H, J=12.20Hz), 8.12(s, 1H). - 400mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 680mg of t-butyl 8-(ethoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2g of Amberlite® IRA-420 were added to 15ml of acetonitrile and thereto 1.5ml of triethylamine was added dropwise and the resulting mixture was refluxed for 5 days and filtered. The filtrate was concentrated under reduced pressure and to the resulting residue 10ml of isopropanol was added and the resulting solution was stirred for 1 hour at room temperature. The precipitated solid was filtered and dried to give 380mg of the titled compound(yield: 51.1%).
m.p. : 235∼236°C
1H-NMR(CDCl3, ppm): 0.98(bs, 2H), 1.15∼1.23(m, 5H). 1.34(s, 9H), 3.26∼ 3.30(m. 1H). 3.86(d, 2H), 3.93(s, 2H), 4.06∼4.12(m, 4H), 4.28(s, 2H), 8.53(s, 1H). - 350mg of 7-[2-(t-buthoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid was dissolved in 5ml of dichloromethane and thereto 0.6ml of trifluoroacetic acid was added dropwise. The mixture was stirred for 5 hours at room temperature and thereto 10ml of ethylether was added. It was stirred additionally for 1 hour and thus precipitated solid was filtered, dissolved in 5ml of diluted NaOH and neutralized with diluted hydrochloric acid. The precipitate thus obtained was filtered and dried. The resulting solid was added to 5ml of 1N-methanesulfonic acid in ethanol and stirred for 1 hour. Thus obtained precipitate was filtered and dried to give 185g of the titled compound(yield : 47.8%).
m.p. : 228∼229°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 0.97(s, 2H), 1.14(d, 2H), 2.48(s, 3H), 3.57(bs, 1H), 3.88(s, 3H), 4.06∼4.17(m, 4H), 4.40(s, 2H), 4.49(s, 2H), 7.88(d, 1H, J=12.67Hz), 8.49(s, 1H). - 175mg of 7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cy clopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolincarboxylic acid was dissolved in 5ml of dichloromethane and thereto 1ml of trifluoroacetic acid was added added dropwise. The resulting mixture was stirred at room temperature for 18 hours, and thereto 10ml of ethylether was added. The resulting precipitate was filtered and dried. Thus obtained solid was dissolved in 2ml of diluted NaOH and neutralized with diluted hydrochloric acid, and the resulting precipitate was filtered and dried. The solid thus obtained was added to 2ml of 1N-methanesulfonic acid in ethanol and stirred at room temperature for 3 hours. The precipitate was filtered and dried to give 35mg of the titled compound(yield : 28.5%).
m.p. : 216∼217°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 1.04(s, 2H), 1.22(d, 2H), 2.45(s, 3H), 3.62(bs, 1H), 3.84(s, 3H), 4.06∼4.18(m, 6H), 4.23(s, 2H), 7.10(d, 1H, J=7.15Hz), 7.76(d, 1H, J=14.27Hz), 8.52(s, 1H). - 150mg of 7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was dissolved in 5ml of dichloromethane and thereto 1ml of trifluoroacetic acid was added dropwise. The mixture was stirred for 5 hours at room temperature and thereto 10ml of ethylether was added. It was additionally stirred for 1 hour, and thus precipitated solid was filtered and dried. Thus obtained solid was dissolved in 5ml of diluted sodium hydroxide and neutralized with diluted hydrochloric acid. The resulting precipitate was filtered and dried to give 115mg of the titled compound(yield : 87.4%).
m.p. : 205∼207°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 1.16(s, 4H), 3.87∼3.97(m, 4H), 4.06∼ 4.33(m, 6H), 4.39(s, 2H), 7.77(d, 1H, J=13.15Hz), 8.63(s, 1H). - 150mg of 7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-6-fluoro-8-chloro-4-oxo-1,4-dihydro-3-quinolinecaboxylic acid was dissolved in 5ml of dichloromethane and thereto 0.2ml of trifluoroacetic acid was added dropwise. The mixture was stirred for 18 hours at room temperature, and thereto 10ml of pyridine and 10ml of water were added. It was distilled under reduced pressure to remove dichloromethane and stirred for 1 hour. The precipitated solid was filtered and dried to give the titled compound(67mg).
yield : 54.7%
m.p. : 220∼221°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 0.95(s, 2H), 1.16(d, 2H), 3.89(s, 3H), 4.02∼4.06(m, 4H), 4.13∼4.23(m, 4H), 4.34(bs, 1H), 7.92(d, 1H, J=12.44Hz), 8.82(s, 1H). - 420mg of 7-[2-(t-Butoxycabonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cy clopropyl-5-amino-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was dissolved in 10ml of dichloromethane and thereto 1ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 18 hours, and thereto 10ml of pyridine was added. It was distilled under reduced pressure. The residue was purified by silica gel chromatography(chloroform:methyl alcohol:water=6:2:0.2). Thus obtained solid was added to 2ml of 1N-methansulfonic acid in ethanol, stirred for 3 hours at room temperature. The precipitated solid was filtered and dried to give the titled compound(165mg)
yield : 39.6%
m.p. : 238∼239°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 1.09(bs, 4H), 2.49(s, 3H), 3.89(s, 3H), 3.92∼3.99(m, 1H), 4.08∼4.20(m, 6H), 4.35(s, 2H), 8.50(s, 1H). - 90mg of 7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2,G-diazaspiro[3,4]oct-6-yl]-1-(2, 4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was dissolved in 5ml of dichloromethane and thereto 0.1ml of trifluoroacetic acid was added dropwise . The mixture was stirred at room temperature for 12 hours and thereto 5ml of pyridine was added. The mixture was distilled under reduced pressure to remove dichloromethane and thereto 5ml of water was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered and dried, and added to 2ml of 1N-methansulfonic acid in ethanol and stirred at room temperature for 1 hour. Thus precipitated solid was filtered and dried to give the titled compound(45mg).
yield : 43.1%
m.p. : 216∼217°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 2.49(s, 6H), 3.74∼4.09(m, 11H), 5.93(d, 1H), 7.24(m, 1H), 7.45(m, 1H), 7.88(m, 1H), 7.89(d, 1H, J=14.40Hz), 8.60(s, 1H). - 140mg of 7-[2-(t-Butoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-(2 ,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxyli c acid was dissolved in 5ml of dichloromethane and thereto 0.2ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 12 hours and thereto 5ml of pyridine was added. It was distilled under reduced pressure to remove dichloromethane and thereto 5ml of water was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered and dried. Thus obtained solid was added to 2ml of 1N-methansulfonic acid in ethanol and stirred at room temperature for 1 hour. The precipitate was filtered and dried to give the titled compound(95mg).
yield : 68.3%
m.p. : 201∼202°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 2.49(s, 3H), 3.85(s, 3H), 3.88∼ 4.10(m, 8H), 7.23∼7.26(m, 1H), 7.40∼7.46(m, 1H), 7.70∼7.76(m, 1H), 8.07(d, 1H, J=12.44Hz), 8.76(s, 1H). - 380mg of 7-[2-(t-Butoxycarbonyl)-8-(ethoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in 5ml of dichloromethane and thereto 0.6ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 12 hours and thereto 3ml of pyridine was added. It was distilled under reduced pressure to remove dichloromethane and 1ml of water was added thereto. It was stirred at room temperature for 2 hours. Thus precipitated solid was filtered and dried. The resulting solid was added to 2ml of 1N-methansulfonic acid in ethanol and stirred at room temperature for 1 hour. The precipitate was filtered and dried to give 220mg of the titled compound(yield : 58.3%).
m.p. : 211∼212°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 1.02(bs, 2H), 1.19∼1.28(m, 5H), 2.48(s, 3H), 3.63∼3.68(m, 1H), 4.06∼4.20(m, 5H), 4.38(s, 2H), 4.51(s. 2H), 7.97(d, 1H, J=12.44Hz), 8.55(s, 1H). - 380mg of 7-[2-(t-Butoxycabonyl)-8-(ethoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-5-amino-6,8-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was dissolved in 10ml of dichloromethane and thereto 0.7ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 18 hours and thereto 10ml of pyridine was added. It was distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography(chloroform : methyl alcohol: water = 6 : 2 : 0.2). Thus obtained solid was added to 1.5ml of 1N-methansulfonic acid in ethanol and stirred at room temperature for 3 hours. The resulting precipitate was filtered and dried to give 180mg of the titled compound(yield : 47.1%).
m.p. : 221∼222°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 0.96∼1.02(m, 4H), 1.15(t, 3H, J=7.08Hz), 2.49(s, 3H), 3.87(d, 1H), 3.98∼4.12(m. 8H), 4.22(s, 2H), 8.42(s, 1H). - 300mg of 1-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added to 10ml of ethanol, and thereto 0.2ml of acetic acid was dropped and 42mg of p-formaldehyde was added. The mixture was stirred at room temperature for 30 minutes, and thereto 85mg of sodium cyanoborohydride was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered and dried to give 260mg of the titled compound(yield : 83.7%). m.p. : 225∼227°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 0.95(s, 2H), 1.16(d, 2H), 2.49(s, 3H), 3.58∼3.61(m, 1H), 3.87(s, 3H), 4.08∼4.18(m, 4H), 4.34(s, 2H), 4.46(s, 2H), 7.93(d, 1H, J=12.43Hz), 8.51(s, 1H). - 300mg of 1-Cyclopropyl-5-amino-6,8-difluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4] oct-6-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was added to 10ml of ethanol, and thereto 0.2ml of acetic acid was added dropwise and 44mg of p-formaldehyde was added. It was stirred at room temperature for 30 minutes and thereto 91mg of sodium cyanoborohydride was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered to give 280mg of the titled compound(yield : 90.4%).
m.p. : 220∼222°C
1H-NMR(DMSO-d6+CF3COOD, ppm): 1.15∼1.23(m, 4H), 2.64(s, 3H), 4.05(s, 3H), 4.06∼4.10(m, 1H), 4.20∼4.39(m, 6H), 4.47(s, 2H), 8.62(s, 1H). - In order to evaluate the in vitro antibacterial activities of the compounds prepared in the examples according to the present invention the minimum inhibitory concentrations(MIC, µg/ml) were measured by the 2-fold agar dilution method(Hoechst 345) using the Muller-Hinton agar. 107 cfu/ml of bacteria were inoculated and cultured for 18 hours at 37°C and then the antibacterial activities were measured. For the methicillin resistant strains the activities were measured after 48 hours of cultivation at 30°C. Hoechst Standard strains were used for the testings. The result is shown in the next tables 1 and 2.
In vitro Antibacterial Activity against resistant strains (µg/ml) (µg/ml) Strains \ Compounds Example 1 Example 5 Example 9 Example 11 Ciproflox acin Sparflox acin Staphylococcus aureus 88E 0.049 0.007 0.007 0.007 0.781 0.098 Staphylococcus aureus 121E 0.049 0.013 0.013 0.013 0.781 0.098 Staphylococcus aureus 208E 0.049 0.007 0.013 0.013 0.781 0.098 Staphylococcus aureus 256E 0.025 0.007 0.013 0.007 0.781 0.098 Staphylococcus aureus 690E 0.025 0.007 0.007 0.007 0.391 0.049 Staphylococcus aureus 692E 0.025 0.004 0.007 0.007 0.391 0.049 Staphylococcus aureus 693E 0.049 0.007 0.013 0.013 0.391 0.049 Staphylococcus aureus 694E 0.049 0.007 0.013 0.013 0.391 0.098 Staphylococcus aureus 695E 0.049 0.007 0.013 0.013 0.391 0.049 Staphylococcus aureus 697E 0.013 <0.002 0.004 0.004 0.391 0.049 Staphylococcus aureus 701E 0.049 0.007 0.013 0.013 0.391 0.098 Staphylococcus aureus 703E 0.049 0.007 0.013 0.013 0.391 0.098 Staphylococcus aureus 179 0.781 0.098 0.098 0.195 12.500 6.250 Staphylococcus aureus 241 0.781 0.098 0.098 0.195 12.500 6.250 Staphylococcus aureus 293 0.781 0.098 0.098 0.195 12.500 6.250 Staphylococcus aureus 303 0.781 0.098 0.098 0.195 12.500 3.125 Staphylococcus aureus 8236 0.781 0.098 0.098 0.195 12.500 6.250 Staphylococcus epidermidis 178 1.563 0.391 0.391 0.781 50.000 6.250 Staphylococcus epidermidis 291 1.563 0.391 0.391 0.781 50.000 6.250 - In the acute toxicity test of the quinolonecarboxylic acid derivatives prepared in the examples according to the present invention ICR mice of 23-25g were used. Each group of mice comprised 5 male and 5 female mice and each sample compound was distributed into 5 doses.
After the mice were starved for 24 hours only with water, samples diluted in 0.2ml of 0.1N NaOH and respectively adjusted to a predetermined dose were injected into the vein of mouse tails. After 1 hour from the injection the mice were fed and then during 14 days lethality was observed. - As the result, the values of LD50(mg/kg) of quinolonecarboxylic acid derivatives and its pharmaceutically acceptable salts according to the invention were of over 320, whereby it was proved that the compounds of the invention have high safety as antibacterial agents.
- The quinolonecarboxylic acid derivatives according to the present invention are very safe compounds as having very low toxicity, and they have more improved antibacterial activity than that of known quinolone antibacterial agents against gram positive bacteria, good antibacterial activity against gram negative bacteria and especially excellent antibacterial activity against methicillin resistant bacteria and known quinolone resistant bacteria.
- Accordingly, the quinolonecarboxylic acid derivatives of the present invention are very useful as antibacterial agents.
Claims (8)
- A process for preparing a quinolonecarboxylic acid derivative, which comprises conducting coupling reaction of the compound of formula 2 with the compound of formula 3 under the presence of an acid acceptor to obtain the compound of formula 1: Wherein, A is C-H, C-F, C-Cl, C-O-CH3 or N; Y is H or amino; R1 is cyclopropyl or 2,4-difluorophenyl; R2 is C1-4 alkyl; R3 is H or C1-4 alkyl; and X is a halogen atom.
- The process of claim 2, wherein an ion-exchange resin selected from the group consisting of Amberlite® IRA-420, Amberlite® IRA-900 and Amberlite® IRA-64 is used for increasing the reactivity of the condensation reaction.
- A process for preparing a quinolonecarboxylic acid derivative, which comprises conducting coupling reaction of the compound of formula 2 with the compound of formula 3a under the presence of an acid acceptor to obtain the compound of formula 4, and removing the amine protecting group(P) from the compound of formula 4 to obtain the compound of formula 1 wherein R3 is H, said process optionally further comprising subjecting the compound of formula 1 wherein R3 is H to a reductive alkylation reaction using C1-4 aldehyde to obtain a compound of formula 1 wherein R3 is C1-4 alkyl: Wherein, A is C-H, C-F, C-Cl, C-O-CH3 or N; Y is H or amino; R1 is cyclopropyl or 2,4-difluorophenyl; R2 is C1-4 alkyl; R3 is H or C1-4 alkyl; X is a halogen atom; and P is an amine protecting group.
- A process for preparing the compound of formula 3, which comprises converting the compound of formula 5 to an oxime compound of formula 7, subjecting the oxime compound to cyclization reaction to obtain the compound of formula 13 and subjecting the compound of formula 13 to deprotection reaction, or a reductive alkylation reaction with a lower aldehyde followed by a deprotection reaction to obtain the compound of formula 3: Wherein, R2 is C1-4 alkyl; R3 is H or C1-4 alkyl; and P' is an amino protecting group.
- The process of claim 6, wherein the compound of formula 5 is converted to an oxime compound by reacting it with formaldehyde to obtain the compound of formula 6 and then reacting the compound of formula 6 with alkoxylamine to obtain the alkoxyimino compound of formula 7: Wherein, R2 is C1-4 alkyl; and P' is an amino protecting group.
- The process of claim 6, wherein the cyclization reaction comprises: converting the hydroxy group(-OH) in the compound of formula 7 to leaving group L selected from the group consisting of methansulfonyloxy, p-toluenesulfonyloxy and halogen to obtain the compound of formula 8; reducing an ester group in the compound of formula 8 to an alcohol to obtain an alcohol compound of formula 9; substituting the leaving group L in the compound of formula 9 with an azido group to obtain the compound of formula 10; converting an hydroxy group in the compound of formula 10 to leaving group L to obtain the compound of formula 11; reducing an azido group in the compound of formula 11 to a primary amine to obtain the compound of formula 12; and subjecting the compound of formula 12 to a cyclization reaction to obtain the compound of formula 13: Wherein, R2 is C1-4 alkyl; and P' is an amino protecting group.
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KR19970027806 | 1997-06-26 | ||
KR9727806 | 1997-06-26 | ||
KR19980001609 | 1998-01-20 | ||
KR9801609 | 1998-01-20 | ||
PCT/KR1998/000185 WO1999000393A1 (en) | 1997-06-26 | 1998-06-26 | Quinolone carboxylic acid derivatives |
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EP0994878B1 true EP0994878B1 (en) | 2001-11-28 |
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US (2) | US6313299B1 (en) |
EP (1) | EP0994878B1 (en) |
JP (1) | JP3280388B2 (en) |
KR (1) | KR100566346B1 (en) |
CN (1) | CN1114607C (en) |
AU (1) | AU7940598A (en) |
DE (1) | DE69802692D1 (en) |
WO (1) | WO1999000393A1 (en) |
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DE60037587T2 (en) * | 1999-05-20 | 2008-04-30 | Dong Wha Pharmaceutical Industrial Co. Ltd. | OPTICALLY ACTIVE QUINOLINE-CARBOXYLIC ACID DERIVATIVES WITH A 7-PYRROLIDIN SUBSTITUENT THAT CAUSES THE OPTICAL ACTIVITY AND A METHOD OF MANUFACTURING THE SAME |
CN101541795A (en) | 2006-09-15 | 2009-09-23 | 先灵公司 | Spiro-condensed azetidine derivatives useful in treating pain, diabetes and disorders of lipid metabilism |
MX2009002919A (en) * | 2006-09-15 | 2009-04-01 | Schering Corp | Azetidine and azetidone derivatives useful in treating pain and disorders of lipid metabolism. |
US7902157B2 (en) | 2006-09-15 | 2011-03-08 | Schering Corporation | Azetidine and azetidone derivatives useful in treating pain and disorders of lipid metabolism |
PL2134712T3 (en) * | 2007-04-13 | 2014-01-31 | Dong Wha Pharm Co Ltd | Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza- spiro [3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same |
CN101974578B (en) * | 2010-10-21 | 2014-06-11 | 杭州师范大学 | Method for preparing quinolone type carboxylic acid intermediate through complex enzyme catalytic hydrolysis |
LT2751083T (en) | 2011-08-31 | 2018-03-26 | Otsuka Pharmaceutical Co., Ltd. | Quinolone compound |
KR101882800B1 (en) | 2012-02-28 | 2018-08-01 | 삼성전자주식회사 | Wireless power receiver and method for controlling thereof |
KR101646324B1 (en) * | 2014-03-04 | 2016-08-05 | 동화약품주식회사 | 1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate hydrates and an antibacterial composition comprising their hydrates |
CN103922987B (en) * | 2014-05-04 | 2016-09-28 | 苏州天马精细化学品股份有限公司 | A kind of Zha Busha star intermediate and synthetic method thereof |
KR102213991B1 (en) * | 2014-05-20 | 2021-02-09 | 동화약품주식회사 | An Improved manufacturing method of Zabofloxacin |
CN108570061B (en) * | 2018-08-06 | 2021-03-02 | 沈阳林特制药有限公司 | Preparation method of zabbixing |
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JPS53141286A (en) | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
US4620007A (en) | 1980-09-03 | 1986-10-28 | Bayer Aktiengesellschaft | 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid |
US4670444B1 (en) | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
US4638067A (en) * | 1982-09-09 | 1987-01-20 | Warner-Lambert Co. | Antibacterial agents |
DE3318145A1 (en) | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
US4573170A (en) * | 1984-02-15 | 1986-02-25 | Westinghouse Electric Corp. | Apparatus and method for sampling multiple carrier signals |
JPS62174053A (en) | 1984-11-14 | 1987-07-30 | Otsuka Pharmaceut Co Ltd | Benzoheterocyclic compound and antibacterial agent containing same |
AT392789B (en) | 1985-01-23 | 1991-06-10 | Toyama Chemical Co Ltd | METHOD FOR PRODUCING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES |
US4617308A (en) | 1985-01-25 | 1986-10-14 | Warner-Lambert Company | 7-substituted amino-1-aryl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and derivatives thereof as antibacterial agents |
CA1336090C (en) * | 1988-08-31 | 1995-06-27 | Isao Hayakawa | Spiro-substituted cyclic amines of quinolone derivatives |
KR960011370B1 (en) * | 1991-12-31 | 1996-08-22 | 재단법인 한국화학연구소 | Spiroalkylamine derivatives |
JPH0649059A (en) * | 1992-07-23 | 1994-02-22 | Hokuriku Seiyaku Co Ltd | 7-@(3754/24)5-azaspiro(2,4)heptan-5-yl)-8-alkoxyquinoline-3-carboxylic acid derivative |
JPH0649060A (en) * | 1992-07-23 | 1994-02-22 | Hokuriku Seiyaku Co Ltd | 5-amino-7-@(3754/24)5-azaspiro(2,4)heptan-5-yl)quinoline-3-carboxylic acid derivative |
JPH06199834A (en) * | 1993-01-08 | 1994-07-19 | Hokuriku Seiyaku Co Ltd | Optically active 8-methoxyquinoline-3-carboxylic acid derivative |
CN1041202C (en) | 1993-08-13 | 1998-12-16 | 同和药品工业株式会社 | Novel Quinolone carboxylic acid derivative |
JPH0770110A (en) * | 1993-08-27 | 1995-03-14 | Hokuriku Seiyaku Co Ltd | 5,8-dimethylquinoline-3-carboxylic acid derivative |
ZA946853B (en) * | 1993-09-10 | 1995-04-24 | Daiichi Seiyaku Co | Crystals of antimicrobial compound. |
US5576321A (en) * | 1995-01-17 | 1996-11-19 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
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1998
- 1998-06-26 WO PCT/KR1998/000185 patent/WO1999000393A1/en active IP Right Grant
- 1998-06-26 EP EP98929898A patent/EP0994878B1/en not_active Expired - Lifetime
- 1998-06-26 AU AU79405/98A patent/AU7940598A/en not_active Abandoned
- 1998-06-26 CN CN98806026A patent/CN1114607C/en not_active Expired - Lifetime
- 1998-06-26 JP JP50546499A patent/JP3280388B2/en not_active Expired - Lifetime
- 1998-06-26 KR KR1019980024391A patent/KR100566346B1/en active Protection Beyond IP Right Term
- 1998-06-26 US US09/446,697 patent/US6313299B1/en not_active Expired - Lifetime
- 1998-06-26 DE DE69802692T patent/DE69802692D1/en not_active Expired - Lifetime
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US6552196B2 (en) | 2003-04-22 |
AU7940598A (en) | 1999-01-19 |
JP3280388B2 (en) | 2002-05-13 |
US20020035258A1 (en) | 2002-03-21 |
JP2000513378A (en) | 2000-10-10 |
KR100566346B1 (en) | 2006-11-10 |
CN1114607C (en) | 2003-07-16 |
CN1259952A (en) | 2000-07-12 |
EP0994878A1 (en) | 2000-04-26 |
DE69802692D1 (en) | 2002-01-10 |
KR19990007390A (en) | 1999-01-25 |
US6313299B1 (en) | 2001-11-06 |
WO1999000393A1 (en) | 1999-01-07 |
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